Role of stress of the endoplasmatic reticulum for fetal inflammation

• Applicant: Privatdozent Dr. David Frommhold
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277333310

Sepsis and septic shock is one of the leading causes for morbidity and mortality, especially among extremely premature children. This is at least in part due to impaired immune defense. As part of cellular defense leukocyte recruitment is ontogenetically regulated and enables efficient leukocyte trafficking only late during fetal life. Mis- or unfolded proteins can induce stress of the endoplasmatic reticulum (ER stress) causing an unfolded-protein response (UPR). It is known that ER stress initiates and perpetuates inflammation, notably also by affecting innate immunity and leukocyte recruitment. We now aim to investigate the role of ER stress for inflammation during fetal development in mice using mice deficient in ER stress key molecules and inhibitors of ER stress, like phenylbutyrate (PBA) and tauroursodeoxycholic acid (TUDCA).Infection of amniotic cavity of pregnant mice at gestational age of E13 to E18 is induced by maternal injection of lipopolysaccharide or lipoteichoic acid to mimic early onset sepsis in preterm and neonates by gram-positive and gram-negative bacteria, respectively. To evaluate the degree of inflammation we use a recently developed model of intravital microscopy of the mouse fetus in combination with standard histology of fetal organs, analysis of prematurity and intra- and extrauterine fetal survival. Inhibition of ER stress through maternal application of PBA/TUDCA may exert anti-inflammatory potential in the fetus. To dissect maternal and fetal effects of ER stress inhibition PBA treatment (crossing placenta) will be compared to TUDCA treatment (no placentar crossing). To explore mechanisms linking fetal inflammation with ER stress, mice deficient in key ER stress molecules are used in the above described setting. Gene regulation and expression studies as well as further approaches of gene depletion warrant full mechanistic workup.The results of these experiments should contribute to develop new strategies (i.e. inhibition of ER stress) treating inflammatory diseases in newborns and preterm infants.

• DFG Programme: Research Grants